EP0033536B1

EP0033536B1 - 6(r)-(2-(8'-etherified-hydroxy-2',6'-dimethylpolyhydro-naphthyl-1')-ethyl)-4(r)-hydroxy-3,4,5,6-tetrahydro-2h-pyran-2-ones, the hydroxy acid form of said pyranones, the salts of said acid form, process for preparing the same and an antihypercholesterolemic pharmaceutical composition containing the same

Info

Publication number: EP0033536B1
Application number: EP81100727A
Authority: EP
Inventors: Robert L. Smith; Ta-Jyh Lee
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1980-02-04
Filing date: 1981-02-02
Publication date: 1984-09-12
Also published as: IE51476B1; GR73078B; ES8202549A1; PT72393B; EP0033536A3; EP0033536A2; DK46081A; PT72393A; US4282155A; ES499077A0; IE810167L; DE3165894D1

Description

Summary of the Invention

This invention relates to a group of 6(R)-[2-(8'-etherified-hydroxy-2',6'-dimethylpolyhydro- naphthyl-1')-ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-ones and to the hydroxy acid form of said pyranones and the salts of said acid form.
More specifically, this invention relates to a compound of the structure I_a-e in Table I in which R is:

C_1-18 alkyl, straight or branched chain,
C_4-10 cycloalkyl,
C_2-10 alkenyl,
C_5-10 cycloalkenyl,
C₂-₁₀ alkynyl,
phenyl C_1-13 alkyl,
substituted phenyl C_1-3 alkyl in which the substituent is halogen, such as F, Cl, Br, I, CF₃ or CN, or C_2-10 alkyl having one or more ―O―, ―S―, or
in the chain, and in which the dotted lines X, Y and Z represent possible double bonds, said double bonds being, when any are present, either X and Z together in combination or X, Y or Z alone, together with the free hydroxy acids, formed by opening the lactone ring, of the formula II_a-e in Table I and the pharmaceutically acceptable salts of said free hydroxy acids.

Background of the lnvention

It is known that certain mevalonate derivatives inhibit the biosynthesis of cholesterol, cf. F.M. Singer et al, Proc. Soc. Exper. Biol. Med., 102, 370 (1959) and F.H. Hulcher, Arch. Biochem. Biophys., 146, 422 (1971). Nevertheless, the activity of these known compounds has not always been found to be satisfactory, i.e. to have practical application.
Recently, Endo et al, reported (U.S. Letters Patent 4,049,495, Patent 4,137,322 and Patent 3,983,140) the production of fermentation products which were quite active in the inhibition of cholesterol biosynthesis. This natural product, now called Compactin, was reported by Brown et al. (J. Chem. Soc. Perkin / 1165 (1976)) to have a complex mevalonolactone structure.
More recently Monaghan et al in US 4,231,938 and in European Publication 22,478, which are incorporated herein by reference, reported an even more potent inhibitor, having the structure III_a in Table I isolated from an entirely different fermentation, and a dihydro-III_a designated Compound III_d of equal potency isolated from the same fermentation.
Patchett et al (European Publication 33,537 describe dihydro and tetrahydro derivatives of III_a with structures of Compounds III_b.c.e prepared by the catalytic hydrogenation of III_a.
The preparation of the starting material III_d, as mentioned previously, is described in European Publication 22,478 and is a product of the following fermentation with a strain of Aspergillus terreus, ATCC No. 20542 American Type Culture Collection, Rockville, Maryland, USA, designated MF-4845 in the culture collection of MERCK & CO., Inc., Rahway, New Jersey.

Preparation of Compound Ill_d

A. Fermentation

A tube of lyophilized culture MF-4845 was opened aseptically and the contents suspended in an unbaffled 250 ml Erlenmeyer flask (seed flask) containing approximately 10 ml of the Medium which has the following composition:

The inoculated flask was incubated for 24 hours at 28°C on a 220 rpm shaker (5.08 cm throw). An unbaffled 2 liter Erlenmeyer flask containing 500 ml of the medium and then inoculated with 10 ml of the first stage fermentation growth from the seed mixture. This too was shaken 24 hours at 28°C.
A 0.757 m³ stainless steel fermentation vat was then charged with 485 liters of a medium comprising:
whose pH was adjusted to 7.0. This was sterilized 15 minutes at 121 °C. One liter of the second stage above was then charged and the mixture was incubated at 85 rpm for 12 hours then 130 rpm for 84 hours at 28°C with an air flow of 0.0024 m³/s for 12 hours then 0.0047 m³/s for 84 hours.

B. Isolation

1. Extraction

Two batches of one 0.378 m³ of whole broth were combined, acidified with stirring to pH 4.1 by careful addition of 800 ml of concentrated hydrochloric acid, and extracted by addition of 0.283 m³ of ethyl acetate and further stirring for two hours.
About 11.34kg of a silicaceous filter aid was then added and the total slurry was pumped through a 24-inch filter press. An additional 0.283 m³ of ethyl acetate was used to wash the press cake and continue the extraction, by reversing the direction of pumping through the press four times. Then all of the wash solvent was discharged from the press and combined with the first filtrate. The two- phase filtrate was allowed to settle, and the water layer removed. The ethyl acetate layer was washed with 0.0378 m³ of deionized water, the phases were allowed to separate and the ethyl acetate extracts were concentrated under vacuum to a residue of about 0.0378 m³.

2. Lactonization

Ethyl acetate extracts from an additional three hundred gal of broth were added to the above extract and the volume was reduced to about thirty gal by vacuum distillation. About 0.189 m³ of toluene was added, and the batch was concentrated under vacuum to 0.121 m³; this step was repeated; then sufficient new toluene was added to bring the volume to 0.283 m^3. Without vacuum, the batch was brought to reflux and maintained there for two hours, with a temperature over 106°C.
This solution was then concentrated under vacuum to a small volume, which was further concentrated to an oily residue in a large rotary evaporator under vacuum.

3. Chromatography on Silica Gel

The extract obtained above was flushed free of other solvents by addition of 0.00757 m³ of methylene chloride and reconcentration to an oil.
The oily residue was dissolved in about 0.0189 m³ of ethyl acetate-methylene chloride (30/70; v/v) mixture, and a slurry was made by addition of 2.8 kg of silica gel.
The slurry was loaded as a level layer on the top of a 30.5 cm x 127 cm silica gel column packed in the same solvent mixture.
Elution was with ethyl acetate-methylene chloride (40/60; v/v) at 800 ml/min. A forerun of 0.0378 m³, then further fractions of 0.0151 m³ each were collected.
Fractions 6-10 inclusive were concentrated under vacuum to an oily residue which was dissolved in hot ethyl acetate, treated with decolorizing carbon, filtered hot, and cooled. Crystals of Compound III_a were filtered off and the mother liquors were concentrated to an oil for further chromatography.

4. Rechromatography on Silica Gel

Mother liquor residues from similar broth extract work-ups equivalent to an additional 2.271 m³ of fermentation production were combined with the above in methylene chloride solution. One-half of this solution was taken for further silica gel chromatography. A small aliquot showed a total solids content of 325 g. The solution was treated with 40 g of decolorizing carbon, filtered, and the cake rinsed with methylene chloride. The combined filtrate and washings were concentrated under vacuum to an oily residue. This was redissolved in 800 ml of ethyl acetate/methylene chloride (30/70; v/v) and slurried with 225 g of silica gel. The slurry was loaded on top of a 14 x 36 cm column bed of silica gel packed in the same solvent mixture. Development was with ethyl acetate/methylene chloride (40/60; v/v). A forecut of three liters was set aside; then fractions of 800 ml each were collected.

5. Chromatography on Reverse-phase Packing

Forty ml from fraction 12 of the above chromatography were concentrated to an oil weighing 500 mg-and the oil redissolved in 5 ml acetonitrile. This acetonitrile solution was charged to a 1.59 cm OD by 6 ft long stainless steel chromatography column packed with preparative reverse-phase liquid chromatography column packing material "Bondapak C18®/PorasilB®" (Waters Associates, Inc., Milford, Mass. 01757). The column was eluted with a mixture of v/v 55% acetonitrile and 45% 0.05 M ammonium phosphate pH 3. The elution volume between 1360 ml and 1700 ml was combined on the basis of refractive index detection. The organic solvent was removed in vacuo and the residual aqueous solution extracted with ethyl acetate. In vacuo removal of the ethyl acetate left 120 mg of compound which crystallized from a concentrated acetonitrile solution yielding crystals of Compound Ill_d, m.p. 129-131°C.
Starting materials III_b, III_c and III_e as mentioned above are described in European Publication 33,537, in accordance with the following Flow Sheet and preparative methods extracted therefrom.

Reactions and Reagents

(1) Hydrogenation at room temperature and one atmosphere over tris-(triphenylphosphine)chloro- rhodium in toluene.
(2) Hydrogenation at room temperature and one atmosphere over 5% palladium on calcium carbonate, in ethanol.
(3) Hydrogenation at room temperature and one atmosphere over platinum oxide in ethyl acetate.

Preparation of 6α[2-(8α-2(S)-methylbutyryloxy-2β,6α-dimethyl-1,2,3,4,6 7,8,8a-octahydronaphthyl-1)ethyl]-4β-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, III_b

A mixture of 50 mg (0.1236 mmol) of Compound III_a and an equal molar amount (114.35 mg, 0.1236 mmol) of tris-(triphenylphosphine)chlororhodium in 10 ml of dry toluene was hydrogenated at room temperature for 6 days, with a total uptake of 14.6 ml of hydrogen. The mixture was evaporated in vacuo to dryness. The red residue was subjected to preparative thin layer chromatography on silver nitrate impregnated silica plates and was developed twice in 10% ethyl acetate-ether system. The yield of Compound III_b was 22.3 mg.
Mass spectrum (M/e) 406 (m⁺)

304 (m - 102)
286 (m - 102 - 18)

nmr (CDCl₃, 300 MHz)

δ4.37 (m, 1H)
4.60 (m, 1 H)
5.34 (d of t, J = 2.5 Hz, 1 H)
5.41 (m, 1 H)

Preparation of 6α[2-(8α-2-(S)-methylbutyryloxy-2β,6α-dimethyl-1,2,3,5,6,7,8,8a-octahydronaphthyl 1)ethyl]-4β-hydroxy,3,4,5,6-tetrahydro -2H-pyran-2-one, III_c

A solution of 80.91 mg (0.2 mmol) of Compound III_a in 10 ml of absolute ethanol, in the presence of an equal weight of 5% Pd on CaC0₃ was hydrogenated at 1 atmosphere until an uptake of one mole equivalent of hydrogen was observed. The catalyst was then removed by filtration and the filtrate was evaporated to dryness (81 mg). After a purification by preparative thin-layer chromatography to remove a small amount of by-product tetrahydro compound, 72 mg of the 1,4 reduction product III_c was isolated.
Mass Spectrum (M/e) 406 (m⁺)

304 (m-102)
286 (304 ― H₂O)

nmr (CDCI₃, 300 MHz)

84.38 (m, 1 H)
4.64 (m, 1 H)
5.28 (d of t, J = 3.5 Hz, 1 H)
5.48 (m, 1 H)

Preparation of 6α-[2-(8α-2(S)-methylbutyryloxy-2α,6β-dimethyl-1,2,3,4,4aα,5,6,7,8,8a-decahydro- naphthyl- 1)-ethyl]-4β -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, III_e

A solution of 80.91 mg (0.2 mmol) of Compound III_a in 10 ml of ethyl acetate was hydrogenated in the presence of an equal weight of platinum oxide at one atmosphere. An exact 2 mole equivalent of hydrogen was consumed within 1 hour. The catalyst was removed by filtration and the filtrate was concentrated to dryness to give an oil. The cis and trans isomers were separated by preparative thin-layer chromatography on silica gel plates (10% ethyl acetate-ether system, bands detected by water spray). The trans isomer III_e appears as the more polar spot, compared to the cis isomer, and 60 mg was isolated.
Mass spectrum (M/e) 408 (m⁺)

323 (m - 85)
306 (m - 102)

nmr (CDCI₃, 300 MHz)

δ4.36 (broad singlet, 1H)
4.59 (m, 1 H)
5.19 (d of t, J = 2.5 Hz, 1 H)

Description of the Invention

We have found that the 8'-acyloxy group in the polyhydronaphthyl moiety in III_a-e, described by the various inventors mentioned above, may be converted to 8'-etherified hydroxy derivatives, Compounds I_a-e which also are potent inhibitors of cholesterol synthesis at the HMG coenzyme A reductase level. More specifically, we have found that compounds of structures I_a-e and II_a-e are potent antihypercholesterolemic agents, less subject to hydrolysis than the prior compounds. Especially preferred are those in which the etherifying group is a branched chain alkyl, such as isobutyl, a halophenyl-C_1-3 loweralkyl, such as fluorobenzyl, loweralkenyl, such as allyl, or lowerqlkynyl, such as propyn-2-yl.
The absolute stereo configuration of these compounds is known from X-ray diffraction. Table I provides a convenient tabulation of these structures and their stereochemical relationship. The reference numerals to the various compounds, including those of the various series of polyhydronaphthyl structures, remain the same throughout these specifications and are so used. Each of the ethers I_a-e, which comprise this invention contains seven or eight chiral centers. The relative and absolute configuration of these asymmetric centers is as depicted in Table I. More specifically, for ether l_a, the Cahn, Ingold, Prelog designations for the absolute configurations are 4(R), 6(R), 1'(S), 2'(S), 6'(R), 8'(S) and 8a'(R) [R.S. Cahn, C.Ingold and V. Prelog, Ang. Chem. Int. Ed. 5, 385 (1966)J.
As is indicated in the formulas I_a-e, all of these compounds have the same spatial orientation of groups at each chiral carbon atom and therefore belong to the same stereochemical series. The R,S designation for each center may not be identical to that found for the ether l_a because of the details of the sequence rules used for determining that designation. In the two ethers I_d and l_e which have an additional chiral carbon atom not present in ether l_a, the hydrogen atom at 4a is in the down (or α) orientation as depicted in Table I, giving a trans ring junction.
The compounds of this invention are highly useful as antihypercholesteremic agents for the treatment of atherosclerosis, hyperlipemia and like diseases in humans. They may be administered orally or parenterally in the form of a capsule, a tablet, an injectable preparation and the like. It is usually desirable to use the oral route. Doses may be varied, depending on the age, severity, body weight and other conditions of human patients but daily dosage for adults is within a range of from about 2 mg to 200 mg (preferably 10 to 100 mg) given in three or four divided doses. Higher doses may be favorably applied as required.
The compounds of this invention also have useful anti-fungal activities. For example, they may be used to control strains of Pencillium sp., Aspergillus niger, Cladosporium sp., Cochliobolus miyabeanus and Helminthosporium cynodnotis. For those utilities they are admixed with suitable formulating agents, powders, emulsifying agents or solvents such as aqueous ethanol and sprayed or dusted on the plants to be protected.
The preparation of the compounds of this invention is outlined in Flow Sheet A. In summary, it starts with the fixing of a t-butyldimethylsilyl protecting group on the 4(R)-hydroxy of the pyranone ring. This product is then subjected to reduction to convert the keto group in the pyranone ring to an alcohol which is subsequently protected with a tetrahydropyranyl group. This reduction and protection is crucial to the synthesis to prevent loss of the 4-silyloxy protecting group during the subsequent step, which is the removal of the acyl-group from the 8-acyloxy on the polyhydronaphthyl ring with lithium aluminum hydride. The 8-hydroxy group so formed is then etherified by reaction with the appropriate reagent. The 2-hydroxy of the pyran ring is then uncovered and reoxidized to a lactone, after which the silyl group is removed from the 4-hydroxy of the pyranone ring.

Flow Sheet Definitions

R, X, Y, Z as defined in the specification.
Reactions

1) Stirring with t-butyldimethylchlorosilane in DMF solution in the presence of imidazole catalyst at 0-50°C.
2) Low temperature (-100 to -60°C) reaction with di-isobutylaluminum hydride in THF.
3) Treatment with dihydropyran and a catalytic amount of pyridinium p-toluenesulfonate in methylene chloride at ambient temperature under an inert atmosphere.
4) Treating with lithium aluminum hydride in refluxing ether at 0-40°C under an inert atmosphere.
5) Stirring at 0-90°C with sodium hydride and RA (A is a halogen or other removable group).
6) Stirring at 1 0-30°C for 40-50 hours with 3 parts of THF to 1 part of acetic acid to one part of water with a catalytic amount of pyridinium p-toluenesulfonate. Time, temperature and ratios are critical to prevent removal of the silyl protecting groups.
7) Oxidation by silver carbonate on in benzene or toluene, at 80-120°C.
8) Treatment with 3 equivalents of tetrabutyl ammonium fluoride and four equivalents of acetic acid in THF at ambient temperature under an inert atmosphere.

The invention can be illustrated by the following Examples:

Example 1

6(R)-[2-(8'(S)-Methoxy-2'(S),6'(R)-dimethyl-1',2',6',7',8',8a'(R)-hexahydronaphthyl-1'(S))-ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (Compound I_a, R = methyl)

A. Preparation of Compound IV_a

A solution of t-butyldimethylsilyl chloride (180 mg 1.2 mmoles) in DMF (2.4 ml) is added to a stirred mixture of Compound Ill_a (300 mg, 0.741 mmol) and imidazole (204 mg, 3 mmol) in DMF (3 ml) while the temperature is maintained at 0°C. The resulting mixture is stirred at room temperature for 16 hours. It is poured into cold water and extracted with ether. The ethereal extract is washed with hydrochloric acid (0.05N) and aqueous sodium bicarbonate (5%), dried over MgS0₄ and filtered. The filtrate is evaporated in vacuo to leave Compound IV_a as a pale yellow, oily residue (0.441 g) which is used directly in the next reaction without further purification: nmr (CDCI₃) 8 0.08 (6H, s), 0.89 (9H, s), 1.08 (3H, d), 1.10 (3H, d), 2.57 (2H, d), 4.3 (H, m), 4.6 (H, m), 5.4 (H, m), 5.54 (H, m), 5.8 (H, d of d), 6.03 (H, d); R_f= 0.81 (silica gel, methylene chloride: acetone = 9:1)

B. Preparation of Compound V_a

A solution of di-i-butylaluminum hydride (1 M in hexane, 0.9 ml) is added via a syringe under a nitrogen atmosphere to a stirred solution of the Compound IV_a prepared above (0.441 g) in THF (15 ml).
During the addition, the temperature is kept at -78°C. The resulting mixture is stirred at -78°C for 0.5 h. Methanol (0.15 ml) is added and the mixture is stirred for 10 minutes. The cooling bath is removed and water (0.6 ml), celite (Trade Mark), (0.6 g) and Na₂SO₄ (3 g) are added. The resulting mixture is stirred at room temperature for 0.5 h and filtered. The collected solid is washed with ether. The combined filtrate and washings are concentrated at reduced pressure to give Compound V_a as a colorless oil (0.45 g) which is used directly in the subsequent reaction without further purification: nmr (CDCl₃) δ 1.07 (3H, d), 1.10 (3H, d), 3.5 ~ 4.2 (2H, m), 4.3 (H, m), 5.1 (H, m), 5.4 (H, m), 5.55 (H, m), 5.8 (H, d of d), 6.05 (H, d); R_f= 0.48 (silica gel, methylene chloride: acetone = 25:1)

C. Preparation of Compound Vl_a

Dihydropyran (0.6 ml, 6.74 mmoles) is added dropwise to a stirred mixture of Compound V_a (0.45 g) and pyridinium p-toluenesulfonate (20 mg, 0.08 mmol) in methylene chloride (2 ml). The resulting mixture is stirred at room temperature under a nitrogen atmosphere for 16 hours. It is poured into cold water and extracted with ether. The ethereal extract is washed with aqueous sodium bicarbonate, dried over MgS0₄ and filtered. The filtrate is concentrated in vacuo to afford an oily residue which is applied to a silica gel column. Elution with methylene chloride:acetone, 50:1 (v/v), produces Compound Vl_a (0.281 g, 0.46 mmole, 62% overall for Steps A―C) as a colorless, glassy oil: nmr (CDCl₃) δ 0.07 (6H, S,), 0.92 (9H, S), 1.07 (2H, d), 1.10 (2H, d), 3.4 ~ 4.1 (4H, m), 4.9 ~ 5.3 (2H, m), 5.4 (H, m), 5.55 (H, m), 5.8 (H, d of d), 6.02 (H, d); R_f= 0.69 (silica gel, methylene chloride:acetone, 25:1).

D. Preparation of Compound VII_a

A solution of Compound Vl_a (96 mg, 0.159 mmol) in ether (2.5 ml) is added to a stirred suspension of lithium aluminum hydride (5 mg, 0.92 mmol) in ether (3 ml). The resulting mixture is heated at reflux under a nitrogen atmosphere for 15 minutes, then cooled to room temperature and stirred for 16 hours. The reaction mixture is treated successively with water (35 µl), 20% sodium hydroxide (35 µl) and water ('105 µl). The resulting mixture is stirred at room temperature for 1 hour and filtered. The filtrate is concentrated to yield an oily residue which is applied to a silica gel column. Elution of the column with methylene chloride:acetone, 50:1 (v/v), gives Compound VII_a (58 mg, 0.111 mmol, 70%) as a colorless, glassy oil: nmr (CDCI₃) 6 0.065 (6H, s), 0.90 (9H, s), 1.20 (3H, d), 3.3~4.4 (5H, m), 4.9 ~ 5.3 (2H, m), 5.57 (H,m), 5.8 (H, d of d), 6.08 (H, d); R_f= 0.33 (silica gel, methylene chloride:acetone, 50:1).

E. Preparation of Compound VIII_a (R = methyl)

To a stirred suspension of sodium hydride (50% oil dispersion, 38 mg, 0.75 mmol, washed with petroleum ether prior to use) in DMF (1 ml) is added a solution of Compound Vil_a (44 mg, 0.084 mmol) in DMF (1 ml) at room temperature under a nitrogen atmosphere. The resulting mixture is heated on a steam bath for 10 minutes and cooled to room temperature. Methyl iodide (0.1 ml, 1.6 mmol) is added and the resulting reaction mixture is heated on a steam bath for 10 minutes. The mixture is cooled to room temperature, poured into cold water and extracted with ether. The ethereal extract is washed with dilute hydrochloric acid and aqueous sodium bicarbonate, dried over MgSO₄ and filtered. The filtrate is evaporated to leave an oily residue which is applied to a silica gel column. Elution with methylene chloride:acetone, 50:1 (v/v), affords Compound Villa (R = methyl), (29 mg, 0.054 mmole, 65%) as a colorless glassy oil: nmr (CDCl₃) δ 0.070 (6H, s), 0.90 (9H, s), 1.15 (3H, d), 3.34 (3H, s), 3.4 ~ 4.1 (4H, m), 4.26 (H, m), 4.9~5.3 (2H, m), 5.5 (H, m), 5.75 (H, d of d), 6.0 (H, d); R_f = 0.37,0.40 (silica gel, methylene chloride:acetone, 50:1)

F. Preparation of Compound IX_a (R = methyl)

Powdered pyridinium p-toluenesulfonate (20 mg, 0.08 mmole) is added in one portion to a stirred mixture of Compound VIII_a from part E (82 mg, 0.153 mmole) in THF (2 ml), acetic acid (0.8 ml) and water (0.6 ml). The resulting mixture is stirred at room temperature under a nitrogen atmosphere for 36 hours. The reaction mixture is poured into cold water and extracted with ether. The ethereal extract is washed with water and aqueous sodium bicarbonate and dried over MgS0₄ and filtered. The filtrate is concentrated in vacuo to provide an oily residue which is subsequently applied to a silica gel column. Elution of the column with methylene chloride:acetate, 50:1 (v/v), first gives the starting tetrahydropyranyl ether (26 mg, 0.049 mmole). Continued elution with the same eluant produces Compound IX_a (R = methyl) (23 mg, 0:051 mmole, 49% based on consumed starting material) as a colorless glassy oil: nmr (CDCl₃) δ 1.14 (3H, d), 3.34 (3H, s), 3.6 ~ 4.4 (3H, m), 5.0 ~ 5.3 (H, m), 5.55 (H, m), 5.80 (H, d of d), 6.00 (H, d); R_f= 0.23 (silica gel, methylene chloride:acetone, 50:1)

G. Preparation of Compound X_a (R = methyl)

A mixture of Compound IX_a from part F (23 mg, 0.051 mmole) and freshly prepared silver carbonate/celite (1.6 g) in benzene (7.5 ml) is heated at reflux under a nitrogen atmosphere for 0.5 h. The reaction mixture is cooled to room temperature. The insoluble solid is collected and washed with ether. The combined filtrate and washings are evaporated on a rotary evaporator to leave Compound X_a (R = methyl) (24 mg) as a glassy oil which is used directly in the next step without further purification: nmr (CDCl₃) δ 0.080 (6H, s), 0.90 (9H, s), 1.12 (3H, d), 2.58 (2H, d), 3.33 (3H, s), 3.7 (H, m), 4.3 (H, m), 4.7 (H, m), 5.5 (H, m), 5.74 (H, d of d), 5.97 (H, d); R_f= 0.41 (silica gel, methylene chloride:acetone, 50:1).

H. Preparation of Compound I_a (R = methyl)

A solution of tetrabutylammonium fluoride trihydrate (0.32 M in THF, 0.75 ml, 0.24 mmole) is added to a stirred mixture of Compound X_a from part G (24 mg) in THF (3 ml) and acetic acid (25 µl, 0.44 mmole). The resulting mixture is stirred at room temperature under a nitrogen atmosphere for 44 hours. The reaction mixture is poured into cold water and extracted with ether. The ethereal extract is washed with aqueous sodium bicarbonate, dried over MgS0₄ and filtered. The filtrate is evaporated in vacuo to yield an oily residue which is applied to a silica gel column. Elution with methylene chloride:acetone, 9:1 (v/v), provides Compound I_a (R = methyl) (17 mg, 0.051 mmole, 100% overall for the last two steps) as a colorless, glassy oil. This oil solidifies on standing at room temperature and is recrystallized from ether-hexane to afford the pure title compound; mp 110―111 °C; R_f= 0.19 (silica gel, methylene chloride:acetone, 9:1); nmr (CDCl₃) δ 0.87 (3H, d), 1.08 (3H, d), 2.66 (2H, m), 3.34 (3H, s), 3.7 (H, m), 4.37 (H, m), 4.7 (H, m), 5.74 (H, d of d), 5.97 (H, d).
Anal. Calcd. for C₂₀H₃₀O₄: C, 71.82; H. 9.04. Found: C, 72.03; H, 9.05.

Example 2

Preparation of 6(R)-[2-(8'(S)-4"-fluorobenzyloxy-2'(S),6'(R)-dimethyl-1',2',6',7',8',8a'(R)-hexa- hydronaphthyl-1'(S))ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (Compound I_a when R = p-fluorobenzyl)

By following the same procedures described in Example 1, Steps E-H, but using an equivalent amount of 4-fluorobenzyl chloride instead of methyl iodide, there are obtained successively:

E. Compound VIII_a (R = p-fluorobenzyl)

R_f= 0.51, 0.57 (silica gel, methylene chloride:acetone, 50:1)
nmr (CDCl₃) δ 1.15 (3H, d), 4.27 (H, d, J = 12 Hz), 4.70 (H, d, J = 12 Hz), 5.5 (H, m), 5.73 (H, d of d), 6.0 (H, d), 6.98 (2H, m), 7.28 (2H, m).

F. Compound IX_a (R = p-fluorobenzyl)

R_f= 0.18 (silica gel, methylene chloride:acetone, 100:1);
nmr (CDCI₃) 8 1.15 (3H, d), 4.30 (H, d, J = 12 Hz), 4.75 (H, d, J = 12 Hz), 5.5 (H, m), 5.8 (H, d of d), 6.0 (H, d), 7.0 (2H, m), 7.32 (2H, m).

G. Preparation of Compound X_a (R = p-fluorobenzyl)

R_f= 0.28 (silica gel, methylene chloride:acetone, 100:1);
nmr (CDCl₃) δ 1.16 (3H, d), 2.52 (2H, d), 3.97 (H, m), 4.30 (H, d, J = 12Hz), 4.72 (H, d, J = 12 Hz), 5.52 (H, m), 5.75 (H, d of d), 6.0 (H, d), 7.0 (2H, d), 7.3 (2H, m).

H. Preparation of Compound I_a (R = p-fluorobenzyl)

R_f= 0.30 (silica gel, methylene chloride:acetone, 10:1);
nmr (CDCl₃) δ 0.86 (3H, d), 1.17 (3H, d), 2.59 (2H, m), 3.90 (H, m), 4.30 (H, d, J = 12 Hz), 4.71 (H, d, J = 12 Hz), 5.53 (_H, m), 5.76 (H, d of d), 6.01 (H, d), 7.03 (2H, t), 7.33 (2H, m).

Example 3

The procedure of Example 1, Step E is followed using an equivalent quantity of the following halides in place of methyl iodide. The product is then taken successively through the procedures of Steps F, G and H of Example 1 to yield the corresponding 6(R)-[2-(8'(S)-RO-2'(S),6'(R)-dimethyl-1',2',6',7',8',8a'(R)-hexahydronaphthyl-1'(S))-ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one:

Example 4

A. The procedure of Example 1 A is followed using Compounds III_b, III_c, III_d and III_e in place of Compound III_a. The products are then successively taken through the procedures of parts B, C, D, E, F, G and H to yield Compounds I_b, I_c. I_a and I_e in which R is methyl.
B. The halides used in Example 3 are used in the procedure of Step E instead of methyliodide and the product is likewise taken through the succeeding steps to yield the products in which RO is the various groups listed in Example 3.

Example 5

Preparation of the hydroxy acid II_a and its sodium salt corresponding to the lactone I_a of Example · 1

To a solution of 10^-4 mole of the Compound I_a in 2 ml of ethanol is added 1 ml of aqueous NaOH (10-⁴ moles; 1 equivalent). After one hour at room temperature, the mixture is taken to dryness in vacuo to yield the sodium salt of Compound II_a.
The sodium salt is redissolved in 2 ml of ethanol-water (1:1) and added to 10 ml of 0.1 N hydrochloric acid from which the liberated hydroxy acid is extracted with ethyl acetate. fhe latter solvent is washed once with water, dried and removed in vacuo with a bath temperature not exceeding 30°.

The hydroxy acid slowly reverts to the lactone on standing.

The other hydroxy acids II_b-e and their salts are prepared substantially as described in Example 5 from the appropriate lactone I_b-e.

Claims

1. A compound of the structure:

in which R is:

C_1-18 alkyl, straight or branched chain,

C_4-10 cycloalkyl,

C_2-10 alkenyl,

C_5-10 cycloalkenyl,

C_2-10 alkynyl,

phenyl C_1-3 alkyl,

substituted phenyl C_1-3 alkyl in which the substituent is halogen, CF₃ or CN, and C_2-10 alkyl having one or more ―O―, ―S―, or

in the chain, in which the dotted lines at X, Y and Z represent possible double bonds, said double bonds, when any are present, being either X and Z in combination or X, Y or Z alone, and the corresponding hydroxy acids of the formula:

and the pharmaceutically acceptable salts.

2. A compound of Claim 1 in the lactone form.

3. A compound of Claim 1 in the free hydroxy acid form or the salts.

4. A compound of Claim 2 in which X and Z are double bonds.

5. A compound of Claim 4 in which R is methyl.

6. A compound of Claim 4 in which R is p-fluorobenzyl.

7. A process for preparing a compound of Claim 1 which comprises:

a) reacting a compound of the structure:

with t-butyldimethylsilane;

b) reducing the product with di-isobutyl aluminum hydride;

c) treating the product of Step (b) with dihydropyran and a catalytic amount of pyridinium p-toluene sulfonate;

d) treating the product of Step (c) with lithium aluminum hydride;

e) etherifying the alcohol from Step (d) by reacting with sodium hydride and a reagent RA in which A is a removable group such as a halogen;

f) stirring the product of Step (e) with a mixture of 3 parts of THF to one of acetic acid and one of water in the presence of a catalytic amount of pyridinium p-toluenesulfonate;

g) oxidation of the product Step (f) with silver carbonate on Kieselghur or diatomaceous earth filter aid; and

h) treating the last product with a mixture of 3 equivalents of tetrabutylammonium fluoride and four equivalents of acetic acid in tetrahydrofuran at room temperature.

8. An antihypercholesterolemic pharmaceutical composition comprising a pharmaceutical carrier and an effective amount of a compound of claim 1.